Mechanisms of maternal high-fat diet induced brain changes

项目摘要 美国超过50%的女性怀孕时超重或肥胖。 母亲的高脂饮食(HFD)和肥胖会造成慢性炎症的环境，并与 一系列对后代不利的后果，包括代谢失调和增加对 精神障碍，如自闭症谱系障碍、焦虑和抑郁。尽管有这些观察， 许多研究都是相关的，并没有提出母亲患肾功能不全或肥胖的机制 子代的精神障碍的发展。胎盘在胎盘和胎盘之间起着至关重要的作用 母体环境和发育中的胎儿大脑，因此独特地准备好翻译母体侮辱 转化为后代的神经结果。胎盘是胎儿前脑中5-羟色胺的主要来源 孕中期，5-羟色胺信号的减少与啮齿动物对应激的易感性增加相关。 重要的是，5-羟色胺水平可以在炎症的背景下降低，我们假设胎盘 母体HFD引起的炎症可能降低胎盘5-羟色胺水平，从而改变 中枢5-羟色胺系统和引起5-羟色胺回路依赖的小鼠行为改变。 初步来看，母体HFD会增加胎盘炎症，特别是在男性。增加了 男性胎盘炎症与胎盘和胎儿前脑5-羟色胺水平降低有关。 此外，男性母体HFD后代也表现出与中枢神经系统紊乱一致的行为改变 5-羟色胺回路功能。因此，在目标1中，我将确定母体HFD诱导的5-羟色胺缺乏症是否 导致男性特有的行为变化。在此基础上，我将使用一个不能 胎盘巨噬细胞对母体HFD诱导的围产儿的促炎反应 炎症是(I)男性特有的5-羟色胺缺乏和(Ii)5-羟色胺回路相关行为的原因 改变。最后，我将讨论母体HFD影响中枢5-羟色胺的可能机制 系统。先前的研究表明，小胶质细胞调节神经发育和行为结果， 宫内小胶质细胞的数量和激活状态影响小胶质细胞对神经元的吞噬作用 祖先。这还没有在5-羟色胺能神经前体细胞的背景下被探索。因此，我会 评估母体HFD子代对5-羟色胺神经元的小胶质细胞吞噬功能是否增加，以及是否如此 结果导致前脑中5-羟色胺水平降低，从而影响母亲对HFD的依赖神经 结果。我希望这个项目通过将三个研究机构联系起来，产生几个新的发现 合作才刚刚开始：(1)母体HFD对性别偏见精神障碍的贡献 发育，(Ii)胎盘在神经发育和疾病中的作用，以及(Iii)小胶质细胞的影响 关于5-羟色胺能神经网络的发展。

Project Summary More than 50% of women in the United States are overweight or obese when they become pregnant. Maternal high-fat diet (HFD) and obesity create an environment of chronic inflammation and are associated with a range of detrimental outcomes for offspring, including metabolic dysregulation and increased susceptibility to psychiatric disorders such as autism spectrum disorder, anxiety, and depression. Despite these observations, many studies are correlative and do not propose a mechanism through which maternal HFD or obesity contribute to psychiatric disorder development in the offspring. The placenta acts as a critical interface between the maternal environment and the developing fetal brain, and as such is uniquely poised to translate maternal insults into neural outcomes in offspring. The placenta is the primary source of serotonin for the fetal forebrain during mid-gestation, and decreased serotonin signaling is correlated with increased vulnerability to stress in rodents. Importantly, serotonin levels can be decreased in the context of inflammation, and we hypothesize that placental inflammation induced by maternal HFD may reduce placental serotonin levels thus altering the development of the central serotonin system and causing serotonin circuit-dependent behavior changes in mice. Preliminarily, we see that maternal HFD increases placental inflammation particularly in males. Increased placental inflammation in males is correlated with decreased placental and fetal forebrain serotonin levels. Moreover, male maternal HFD offspring also display behavior alterations consistent with disrupted central serotonin circuit function. Therefore, in Aim 1, I will determine if maternal HFD-induced serotonin deficiency is causal to male-specific behavior changes. Building upon this, I will then use a mouse model incapable of producing a pro-inflammatory response in placental macrophages to asses if maternal HFD-induced perinatal inflammation is causal to (i) male-specific serotonin deficiency and (ii) serotonin-circuit relevant behavior changes. Finally, I will address a possible mechanism through which maternal HFD affects the central serotonin system. Previous studies have suggested that microglia regulate neural development and behavioral outcomes, and that the number and activation state of microglia in utero influences microglia phagocytosis of neuronal progenitors. This has not been explored in the context of serotonergic neuronal progenitors. Therefore, I will assess if microglia phagocytosis of serotonin neurons is increased in maternal HFD offspring, and whether this results in decreased serotonin levels in the forebrain thus influencing maternal HFD-dependent neurological outcomes. I expect this project to result in several novel findings by bridging three bodies of research that are only beginning to collaborate: (i) the contribution of maternal HFD to sex-biased psychiatric disorder development, (ii) the role of the placenta in neurodevelopment and disease, and (iii) the influence of microglia on the development of the serotonergic neural network.